title: Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients.
abstract: OBJECTIVE
  Pharmacogenetics can be used as a tool for stratified pharmacological therapy in cardiovascular medicine. We investigated whether a predefined combination of the Arg389Gly polymorphism in the adrenergic β(1) -receptor gene (ADRB1) and the Gln27Glu polymorphism in the adrenergic β(2) -receptor gene (ADRB2) could predict survival in carvedilol- and metoprolol-treated chronic heart failure (HF) patients.
  
  
  METHODS
  Five hundred and eighty-six HF patients (carvedilol n= 82, metoprolol n= 195) were genotyped for ADRB1 Arg389Gly (rs1801253) and ADRB2 Gln27Glu (rs1042714). The end-point was all-cause mortality, and median follow-up time was 6.7 years. Patients were classified into two functional genotype groups: group 1 combination of Arg389-homozygous and Gln27-carrier (46%) and group 2 any other genotype combination (54%). Results were fitted in two multivariate Cox models.
  
  
  RESULTS
  There was a significant interaction between functional genotype group and carvedilol treatment (adjusted(1) P= 0.033, adjusted(2) P= 0.040). Patients treated with carvedilol had shorter survival in functional genotype group 1 (P= 0.004; adjusted(1) hazard ratio (HR) 2.67, 95% CI 1.27, 5.59, P= 0.010; adjusted(2) HR 2.05, 95% CI 1.06, 3.95, P= 0.033). There was no interaction between genotype group and metoprolol treatment (P= 0.61), and there was no difference in overall survival between genotype groups (P= 0.69).
  
  
  CONCLUSIONS
  A combination of ADRB1 Arg389-homozygous and ADRB2 Gln27-carrier in HF patients treated with carvedilol was associated with a two-fold increase in mortality relative to all other genotype combinations. There was no difference in survival in metoprolol-treated HF patients between genotype groups. Patients in genotype group 1 may benefit more from metoprolol than carvedilol treatment.
authors.affiliation: Laboratory of Clinical Pharmacology Q7642, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. mortenpetersen@rh.dk
authors.forename: Morten
authors.initials: M
authors.lastname: Petersen
authors.forename: Jon T
authors.initials: JT
authors.lastname: Andersen
authors.forename: Brian R
authors.initials: BR
authors.lastname: Hjelvang
authors.forename: Kasper
authors.initials: K
authors.lastname: Broedbaek
authors.forename: Shoaib
authors.initials: S
authors.lastname: Afzal
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
authors.forename: Steen
authors.initials: S
authors.lastname: Stender
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
authors.forename: Christian
authors.initials: C
authors.lastname: Torp-Pedersen
authors.forename: Henrik E
authors.initials: HE
authors.lastname: Poulsen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use*; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011412:Propanolamines / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D008790:Metoprolol